Taxane derivatives and processes for the preparation thereof

ABSTRACT

A novel taxane derivative with anticancer activity, a process for its preparation and a process for the preparation of 14-β-hydroxy-1,14-carbonate-baccatine III and V derivatives 13-substituted by an isoserine residue.

TECHNICAL FIELD

The present invention relates to a novel taxane useful aschemotherapeutic agent, the pharmaceutical compositions containing itand a process for the preparation of14-β-hydroxy-1,14-carbonate-baccatine III and V derivatives, substitutedat the 13 position by an isoserine residue.

BACKGROUND OF THE INVENTION

Taxanes are one of the most important classes of anticancer drugsrecently developed. The remarkable effectiveness of Paclitaxel and ofits analogue Docetaxel in the treatment of several tumors has focusedresearch on substances with antimicrotubular activity. Taxanes arehowever characterized by a particular action mechanism, in that theypromote the assembly of microtubules and inhibit tubulinedepolymerization.

The main drawbacks of the taxanes presently used are: (a) insolubilityin water, making mandatory the use of specific carriers which can causehypersensitization reactions, (b) toxicities which limit dosages, (c)development of resistance mechanisms. Cell resistance to taxanes hasbeen related to the MDR phenotype (“multidrug resistance”) mediated bythe P-glycoprotein transporter, by tubuline alterations, and by changesin the expression of apoptotic regulatory proteins.

In order to find novel active molecules having higher solubility andbetter tolerability, 14β-hydroxy-10-deacetylbaccatine III and V taxanederivatives have been synthesized.

Some derivatives of 14-hydroxy baccatine III substituted at the13-position by isoserine residues are disclosed in U.S. Pat. No.5,705,508, together with a process for the preparation thereof.

SUMMARY OF THE INVENTION

It has now been found that the compound of formula (I), a14β-hydroxy-1,14-carbonate-baccatine V derivative,

has remarkable cytotoxic and anticancer activities, and is capable ofovercoming the resistance of cell lines expressing the MDR phenotype.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compound of the invention differs from the prior art derivatives dueto the hydroxyl at the 7-position, which in the present case is in alfaconfiguration. 13-(N-Boc-β-Isobutylisoserinyl)-14β-hydroxy-baccatine III1,14-carbonate, corresponding to the derivative referred to in U.S. Pat.No. 5,705,508 as SB-T-101131, can be used as starting product for thepreparation of compound (I). In this case, said baccatine m derivativeis either treated with DBU (diazabicyclo[5,4,0]7-undecene) in methanolor THF or it is simply left in solution with methylene chloride orchlorinated solvents in the presence of aliphatic alcohols such asmethanol, ethanol or propanol with basic allumine for a time rangingfrom one hour to 14 days. The compound having beta configuration at C-7,is converted at neutral or slightly basic pH to the more stable alfaisomer (baccatine V derivative).

Alternatively, compound (I) can be prepared with a process which alsoallows to prepare the corresponding beta epimer at C-7.

Said process (A) comprises the following steps:

-   -   a) transformation of 14β-hydroxy-10-deacetylbaccatine III or V        into the derivative triethylsilylated at the 7-position;    -   b) preparation of the 1,14 carbonate derivative from the product        of step (a);    -   c) selective acetylation of the 10-hydroxyl;    -   d) reaction of the product of step (c) with (4S,        5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylic        acid;    -   e) cleavage of the triethylsilyl and dimethoxybenzylidene        protective groups from the product of step (d).

According to a preferred embodiment of process (A), triethylchlorosilaneis used as silylating agent in step (a), whereas the 1,14 carbonatederivative in step (b) is prepared using phosgene in toluene in a 3:1methylene chloride/pyridine solution under nitrogen atmosphere. In thefollowing step (c) 14-β-hydroxy-10-deacetylbaccatine III or V7-Tes-1,14-carbonate is salified with LiHMDS in anhydrous THF, therebyobtaining the 10-hydroxy derivative lithium salt, which is subsequentlyacetylated with acetyl chloride. The condensation reaction between14-β-hydroxy-7-Tes-1,14-carbonate-baccatine III or V and (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylicacid (step (d)) is carried out in anhydrous apolar organic solvent, inthe presence of a base and a condensing agent such asdicyclohexylcarbodiimide (DCC).

Finally, in step (e) triethylsilyl is removed with pyridinium fluoridein acetonitrile/pyridine solution under nitrogen, whereas thedimethoxybenzylidene group is removed in methylene chloride solvent byaddition of methanol HCl and subsequently of NaHCO₃.

The step sequence of the process described can be inverted thusobtaining the final product in as much comparable yields. Saidalternative process (B) comprises the following steps:

-   -   a′) selective acetylation of the hydroxyl at C-10 of        14β-hydroxy-10-deacetylbaccatine III or V;    -   b′) preparation of the 1,14 carbonate derivative from the        product of step (a′)    -   c′) silylation of the hydroxyl at C-7;    -   d′) reaction of the product of step (c′) with (4S,        5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylic        acid;    -   e′) cleavage of the triethylsilyl and dimethoxybenzylidene        protective groups from the product of step (d′).

The latter process involves a number of advantages such as thepossibility to obtain the desired synton (1,14-carbonate-7-Tes-baccatineIII or V) without chromatographic purifications, merely bycrystallization.

According to a preferred embodiment, the selective acetylation of step(a′) is carried out with acetic anhydride in the presence of cerium,scandium, ytterbium salts, preferably CeCl₃.7H₂O, whereas the remainingsteps are carried out as indicated above.

The present invention also comprises, as intermediate products of theprocess for the preparation of 14β-hydroxy-1,14-carbonate baccatine IIIor V, the following compounds: 14β-hydroxy baccatine III or V,14β-hydroxy baccatine III or V 1,14 carbonate,14-β-hydroxy-7-Tes-10-deacetylbaccatine III or V,14-β-hydroxy-7-Tes-baccatine III or V, 14-β-hydroxy-7-Tes-baccatine IIIor V 1,14-carbonate.

A further aspect of the invention relates to a process for thepreparation of (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylicacid, according to the following scheme:

Said process comprises the following steps:

-   -   a) protection of the amino group of leucinol with Boc;    -   b) transformation of N-Boc-L-leucinol into N-Boc-L-leucinal;    -   c) preparation of the cyanhydrin of the product from step (b);    -   d) transformation of the cyanhydrin nitrile into the        corresponding carboxylic acid;    -   e) formation of the carboxylic acid methyl ester;    -   f) purification of the (2R,        3S)-3-(N-Boc)amino-2-hydroxy-5-methylhexanoic acid methyl ester;    -   g) condensation of the product of step (f) with        2,4-dimethoxybenzaldehyde dimethyl acetal;    -   h) transformation of the (4S,        5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylic        acid methyl ester into the corresponding carboxylic acid.

According to a preferred embodiment, in step (a) leucinol is reactedwith Boc-anhydride, and subsequently oxidized to aldehyde in DMSO/CH₂Cl₂solvent using oxalyl chloride at a temperature below −60° C.,neutralizing the formed acid with triethylamine, or oxidizing it withsodium hypochlorite at −2 to −5° C. The cyanhydrin of step (c) isprepared by substituting the sulfonic group of the intermediate1-hydroxy-2-(N-Boc)amino-4-methylpentanesulfonate by the cyanide ion.The cyanhydrin is then hydrolyzed to the corresponding carboxylic acidin step (d) by refluxing in concentrated hydrochloric acid.

In step (e), (2R/S,3S)-3-(N-Boc)amino-2-hydroxy-5-methylhexanoic acid isconverted in the corresponding methyl ester by reaction withdiazomethane in ethereal solution. In step (f), diastereomer (2R, 3S) ispurified by crystallization from cyclohexane or an hexane/toluenemixture. Step (g) is carried out in THF in the presence of pyridiniump-toluenesulfonate removing the developed methanol, after completion ofthe reaction, pyridinium p-toluenesulfonate is neutralized withbicarbonate. In step (h), the ester is hydrolysed in a methanol/watermixture with potassium carbonate. The reaction mixture is subsequentlyacidified and the final product is extracted with methylene chloride.

The invention also comprises (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylicacid as an intermediate for the synthesis of baccatine III and Vderivatives substituted at the 13-position by a N-Boc-β-isobutylserinylresidue.

The novel taxane of the present invention showed a strong anticanceractivity against cancerous cells of breast, lung, ovary, colon,prostate, kidney, pancreas, and also against cells resistant to theknown anticancer drugs such as adriamycin, vinblastine and platinumderivatives.

Therefore, the invention relates to pharmaceutical formulationscontaining an effective amount of the compound of the invention,together with pharmacologically acceptable carriers and excipients. Moreparticularly, the compound can be formulated in the form of tablets,powders, granulates, capsules, injectables, solutions, suppositories,emulsions, dispersions, and the like. For the intravenousadministration, mixtures of Chemophor L and ethanol, polysorbate andethanol or liposome formulations prepared with natural or syntheticphosphatidylcholine, or mixtures of natural phospholipids in thepresence of cholesterol are mainly used; for the oral administration.,soft-gelatin capsules in which the product is solubilised inpolysorbates, PEG or mixtures thereof, optionally in the presence ofphospholipids, are preferably prepared. Compound (I) can be administeredto humans at concentrations from 50 to 500 mg/m².

The following examples illustrate the invention in greater detail.

EXAMPLE 1 Synthesis of 13-(N-Boc-β-isobutylserinyl)-14β-hydroxybaccatineIII, 1,14 carbonate

43.26 g of 14β-hydroxy-deacetylbaccatine III together with 22.3 ml ofN-methyl-imidazole were dissolved in 230 ml of DMF in a 500 ml glassround-bottom flask; this solution was added under strong stirring atroom temperature in 1 h with 14 ml of triethylchlorosilane. When thereaction was over, the reaction mixture was poured into 2 L of waterunder strong stirring. An abundant precipitate formed, which was left at4° C. overnight. The precipitate was then filtered, thoroughly washingwith water and subsequently with n-hexane. After drying under vacuum48.1 g of 7-Tes-10-deacetylbaccatine III (XII) were obtained containinga small percentage of the 7,10-derivative, having the followingchemical-physical characteristics:

¹H NMR (CDCl₃ 200 MHz): δ (ppm) 0.55 (6H, t, J=7.8 Hz, 7-OTES CH₂), 0.94(9H, q, J=7.8 Hz, 7-OTES CH₃), 1.18 (3H, s, C16H₃), 1.20 (3H, s, C17H₃),1.77 (3H, s, C19H₃), 1.90 (1H, ddd, J=2.4, 10.8, 13.2 Hz, C6Hβ), 2.12(3H, d, J=1.6 Hz, C18H₃), 2.31 (3H, s, 4-OCOCH₃), 2.48 (3H, ddd, J=14.3,9.8, 6.5 Hz, C6Hα), 2.73 (1H, d, J=5.5 Hz, OH) 3.79 (1H, d, J=7.1 Hz,C3H), 4.20 (1H, dd, J=1.0, 8.3 Hz, C20Hβ), 4.31 (1H, d, J=8.6 Hz,C20Hα), 4.39 (1H, dd, J=6.4, 10.7 Hz, C7H), 4.77 (1H, d, J=5.8 Hz,C14H), 4.94 (1H, dd, J=2.1, 9.7 Hz, (C5H), 5.05 (1H, m, C13H), 5.13 (1H,d, J=1.9 Hz, C10H), 6.05 (1H, d, J=7.3 Hz, C2H), 7.41-8.09 (5H, m, Ph).

Mass Spectrum (NH₃, DEP/CI, positive lions): (m/z) 718 [(M+NH₄)⁺, 100%],701 [M+H)⁺, 39%].

The resulting compound was dissolved in 300 ml of a methylenechloride/pyridine 3:1 mixture under nitrogen atmosphere; this solutionwas added under with stirring to a phosgene solution (214 ml of a 1.9Msolution in toluene) precooled at −10° C., keeping temperature from −5to −10° C. during the addition.

The reaction mixture was stirred for 30′, then shaken with 700 ml of aNaHCO₃ saturated solution keeping temperature below or at 2° C. Thephases were separated and the organic phase was washed to removepyridine. The organic phase was dehydrated over MgSO₄ and concentratedto dryness 46.6 g of 10-deacetylbaccatine III 7-Tes-1,14-carbonate wereobtained which could be directly used for the following reactions.

31 g of the compound were dissolved in 250 ml of strictly anhydrous THF;the solution was cooled at −50° C. and added with 48 ml of a 1M LiHMDSsolution in 2 minutes and stirred for 20 minutes at the sametemperature. 3.7 g of acetyl chloride were added during 40 min. withstirring. The reaction temperature was left to raise to 0° C. keepingstirring for 2 h. Upon completion of the reaction, the mixture wastreated with a NH₄Cl saturated solution and diluted with ethyl acetate.The phases were separated and the aqueous solution was diluted withethyl acetate until exhaustion of the product. The combined organicphases were washed with water then dried over MgSO₄ and concentrated todryness. 33 g of 14β-hydroxy-7-Tes-1,14-carbonate-baccatine III wereobtained, impure due to the compounds of the preceding reactions. Thiscompound was chromatographed on silica gel eluting the pure product withan ethyl acetate/CH₂Cl₂ 9:1 mixture. 30 g of the desired product (XIII)were obtained, having the following characteristics:

¹H NMR (CDCl₃ 200 MHz): δ (ppm)=0.55 (6H, t, J=7.8 Hz, 7-OTES CH₂), 0.95(9H, q, J=7.8 Hz, 7-OTES CH₃), 1.16 (3H, s, C16H₃), 1.32 (3H, s, C17H₃),1.77 (3H, s, C19H₃), 1.88 (1H, ddd, J=2.4, 10.8, 13.2 Hz, C6Hβ), 2.21(3H, d, J=1.6 Hz, C18H₃), 2.19 (3H, s, 10-OCOCH₃), 2.31 (3H, s,4-OCOCH₃), 2.48 (3H, ddd, J=14.3, 9.8, 6.5 Hz, C6Hα), 2.73 (1H, d, J=5.5Hz, OH) 3.72 (1H, d, J=7.1 Hz, C3H), 4.20 (1H, d, J=8.3 Hz, C20Hβ), 4.31(1H, d, J=8.6 Hz, C20Hα), 4.46 (1H, dd, J=6.4, 10.7 Hz, C7H), 4.79 (1H,d, J=5.8 Hz, C14H), 4.94 (1H, dd, J=2.1, 9.7 Hz, (C5H), 5.02 (1H, m,C10H), 5.05 (1H, m, C13H), 6.09 (1H, d, J=7.3 Hz, C2H), 7.41-8.09 (5H,m, Ph).

Mass Spectrum (NH₃, DEP/CI, positive ions): (m/z) 759 [(M+NH₄)⁺, 19%],743 [M+H)⁺, 100%].

20 g of 14β-hydroxy-7-Tes-1,14-carbonate-baccatine III together with a300 ml of strictly anhydrous toluene were placed in a 1 L round-bottomflask, 10 g of (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazoli-dine-5-carboxylicacid and 2 g of N,N-dimethylaminopyridine (DMAP) and 9.5 g ofdicyclohexylcarbodiimide (DCC) dissolved in CH₂Cl₂ were added. Thereaction mixture was refluxed for 3 h, then cooled, the ureic productwas precipitated off and mother liquors were washed with a NaHCO₃saturated solution to remove the unreacted acid, then with dilutedhydrochloric acid to remove DMAP and finally again with NaHCO₃ toneutrality. The organic phase was concentrated to dryness to obtain 41.5g of product which could be directly used in the subsequent step.

40 g of this compound were deprotected in two steps, by removing firstTes and then 2,4-dimethoxybenzaldehyde. 40 g of the compound weredissolved in 100 ml of an acetonitrile/pyridine mixture (80:100) undernitrogen and cooled at 0° C.; 13 ml of pyridinium fluoride were addedand the whole was left under stirring for 24 h. The solution was pouredinto 2 L of water and the product was filtered and dried under vacuum.

The residue was dissolved in 60 ml of methylene chloride and thissolution was added with 40 ml of 0.6N HCl in methanol under strongstirring and at 0° C. The reaction mixture was left for 2 h understirring, then diluted with 150 ml of methylene chloride and shaken witha NaHCO₃ solution adjusting pH to 6-7. The organic phase wasconcentrated to dryness and the residue was crystallized from acetonehexane. After drying, 16 g of13-(N-Boc-β-isobutylisoserinyl)-14β-hydroxybaccatine-1,14-carbonate wereobtained, having the following chemico-physical and spectroscopicalcharacteristics:

Formula: C₄₄H₅₇NO₁₇

Aspect: white powder.

Melting point: 245° C.

TABLE 1 Chemical shifts (ppm) ¹H NMR in CDCl₃ solution (200 MHz) H Ppm,multiplicity (Hz) H Ppm, multiplicity (Hz)  2 6.09-d (7.8) 2′ 4.30-dd(6.4; 3.2)  3 3.68-d (7.4) 3′ 4.08-m  5 4.91-dd (9.7; 2.5)  4′a 1.21-m  6α 2.52-ddd (14.8; 9.8; 6.9)  4′b 1.43-m  6β 1.86-m 5′ 1.65-m  74.37-m 6′ 0.96-d (6.3) 10 6.25-s 7′ 0.95-d (6.3) 13 6.44-d (broad, 6.9)4-OCOCH ₃ 2.40-s 14 4.84-d (6.9) 10-OCOCH ₃ 2.22-s 16 1.25-s Boc 1.35-s17 1.32-s o-benzoyl 8.01-m 18 1.87-d (1.6) m-benzoyl 7.46-m 19 1.69-sp-benzoyl 7.58-m   20α 4.27-d (8.4) 3-NH 4.72-d (9.0)  20β 4.20-d (8.4)

TABLE 2 Chemical shifts (ppm) ¹³C NMR in CDCl₃ solution (50.308 MHz) Cppm, multiplicity C ppm, multiplicity 9 201.8-s  8 58.2-s  1′ 172.6-s  3′ 51.2-d 4-OCOCH₃ 170.5-s  3 44.6-d 10-OCOCH₃ 170.2-s 15 41.3-s2-COPh 164.3-s  4 39.9-t C—O (Boc) 155.8-s  6 34.9-t C═O (carbonate)151.4-s (CH₃)₃C Boc 27.7-q 12  139.4-s 17 25.5-q 11  133.1-s 16 22.6-q(Me)₃ C (Boc) 80.0-s 4-OCOCH₃ 22.0-q 5 83.8-d 10-OCOCH₃ 20.2-q 1 87.7-s  5′ 24.3-d 4 80.0-s   6′ 22.7-q 2 69.0-d   7′ 21.6-q 20  75.5-t 1814.6-q  2′ 73.3-d 19 9.8-q 7 71.2-d q-benzoyl 127.5-s 10  74.3-do-benzoyl 129.5-d 13  74.1-d m-benzoyl 128.6-d 14  79.1-d p-benzoyl133.7-d

Mass Spectra: (NH₃, DEP/CI, positive ions): (m/z) 889 [(MNH₄)⁺], 832[(MNH₄—(CH₃)₃C)⁺], 772 [(MNH₄—BocNH₂)⁺].

(NH₃, DEP/CI, negative ions): (m/z) 871 (M⁻), 260 (side chain)

Infrared Spectrum (KBr disc): 3521, 3321, 2971, 2953, 1826, 1762, 1706,1526, 1366, 1238, 1165, 1072, 723 cm⁻¹

UV Spectrum (MeOH): 231, 276 and 284 nm;

E_(1%) at 231 nm=180.99

E_(1%) at 276 nm=14.094

E_(1%) at 284 nm=12.182

EXAMPLE 2 Synthesis of 13-(N-Boc-β-isobutylserinyl)-14β-hydroxybaccatineV, 1,14 carbonate

5 g of 13-(N-Boc-β-isobutylserinyl)-14β-hydroxybaccatine III, 1,14carbonate were dissolved in 500 ml of toluene under argon atmosphere,completely deoxygenating the solution; 80 mg of DBU(diazabicyclo[5,4,0]7-undecene) were added and the reaction mixture wasrefluxed for 1 hour under argon atmosphere. The solution was dilutedwith 100 ml of ethyl acetate and washed with water. The organic phasewas evaporated to dryness to obtain 4.5 g of13-(N-Boc-13-isobutylserinyl)-14β-hydroxybaccatine V 1,14 carbonatehaving the following chemical-physical and spectroscopicalcharacteristics:

Formula: C₄₄H₅₇NO₁₇

Aspect: white powder

Melting point: 245° C.

TABLE 3 Chemical shift (ppm) ¹H NMR in CDCl₃ solution (200 MHz) H Ppm,multiplicity (Hz) H Ppm, multiplicity (Hz) 2 6.18 d (7.9)  2′* 4.75 d(8.6) 3 3.80 d (7.8) 3′ 4.01 m 5 4.93 dd (7.8; 4.8)  4′a 1.25 m 6 2.23 m 4′b 1.48 m 7 3.76 m 5′ 1.67 m 10 6.79 s 6′ 0.99 d (6.4) 13 6.44 d (6.7)7′ 0.97 d (6.4) 14 4.88 d (7.0) 4-OCOCH ₃ 2.58 s 16 1.29 s 10-OCOCH ₃2.20 s 17 1.31 s Boc 1.37 s 18 1.87 d (1.5) o-benzoyl 8.06 m 19 1.71 sm-benzoyl 7.49 m 20 4.38 s p-benzoyl 7.61 m 3′-NH* 4.60 d (11.2) *Can bereversed

TABLE 4 Chemical shift (ppm) ¹³C NMR in CDCl₃ solution (50.308 MHz) CPpm, multiplicity C Ppm, multiplicity 9 206.1 s  8 58.2 s  1′ 173.1 s  3′ 52.0 d 4-OCOCH₃ 172.7 s  3 40.4 d 10-OCOCH₃ 169.3 s 15 41.5 s2-COPh 165.1 s   4′ 40.6 t C═O (Boc) 156.6 s  6 35.2 t C—O (Carbonate)152.1 s (CH₃)₃C 28.4 q (Boc) 12  137.6 s 17 25.4 q 11  134.0 s 16 22.4 q(Me)₃ C (Boc)^(§) 81.7 s 4-OCOCH₃ 22.7 q 5 82.7 d 10-OCOCH₃ 18.6 q 188.5 s   5′ 25.1 d  4^(§) 80.7 s   6′ 23.4 q 2 69.9 d   7′ 20.9 q 20 77.2 t  18{acute over ( )} 15.2 q  2′° 74.6 d  19{acute over ( )} 16.2 q 7° 77.6 d q-benzoyl 128.3 s 10°  74.2 d o-benzoyl 160.2 d 13°  76.0 dm-benzoyl 128.2 d 14  79.9 d p-benzoyl 134.4 d *, ^(§), °, {acute over( )} = Can be reversed

Mass Spectrum (TSP+): (m/z) 872 (MH⁺); 816 (MH₊—(CH₃)₂═CH₂); 772(816-CO₂); 756 (816-AcOH); 712 (772-AcOH)

Infrared Spectrum (KBr disc): 3450, 2963, 1813, 1740, 1702, 1247, 1091,710 cm⁻¹

UV Spectrum (MeOH): 200 e 230 nm

E_(1%) at 200 nm=370.9

E_(1%) at 230 nm=193.2

EXAMPLE 3 Preparation of (4S,5R)-N-Boc-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylicacid

Preparation of N-Boc-L-leucinol (III):

46.8 g of L-leucinol II (400 mmol) were dissolved in 300 ml of CH₂Cl₂ ina 2 l three-necked round-bottom flask equipped with mechanical stirrer,thermometer and dropping funnel. The stirred solution was then addeddrop by drop at room temperature with the solution of Boc anhydride(87.2 g, 400 mmol) in CH₂Cl₂ (100 mL) in 90 minutes. During the additionof the first 25% of Boc-anhydride, the reaction was exothermic and itreached 20-30° C. yielding a slurry which turned clear after stirring atroom temperature for a further three hours. The whole was left at roomtemperature overnight. The solvent was evaporated under high vacuum toobtain the desired product as a thick oil in a quantitative yield (87g). The product was subsequently treated without further purification.

Preparation of N-Boc-L-leucinal (IV)

A solution of oxalyl chloride (26.274 mL, 300 mmol) in 130 ml ofmethylene chloride precooled at −60/−65° C. was slowly added with DMSO(28.4 mL, 400 mmol).

The solution turned clear when the addition of DMSO was completed. After20 minute stirring at the same temperature the reaction mixture wassubsequently treated with a solution of alcohol III (43.7 g, 200 mmol)in CH₂Cl₂ (200 mL) for 25 min keeping temperature below −60° C. Duringthe addition of the alcohol the reaction mixture became cloudy, and awhite precipitate formed. After 20-25 minutes of stirring at the sametemperature a solution of triethylamine (112 mL, 800 mmol) in CH₂Cl₂(100 mL) was added dropwise in 40 minutes keeping temperature between−68 and −62° C. The reaction mixture was then stirred at between −60 and−65° C. for a further 50 minutes. TLC of the reaction mixture carriedout using 8% methanol in CH₂Cl₂ as eluent detected no starting product.

The cold solution was then poured into 800 ml of an iced solutioncontaining 68 g (0.5 mol) of KHSO₄. The organic layer was separated andthe aqueous phase extracted with CH₂Cl₂ (100 mL). The combined organicphases were washed with aqueous KHSO₄ (5%, 1×200 mL), brine (100 mL, 50mL) and concentrated to half volume (−250 mL). Said material was useddirectly in the subsequent step.

Aldehyde (V) Bisulfite Compound Derivative

The methylene chloride solution of the aldehyde (IV) in a 2 lthree-necked round-bottom flask equipped with mechanical stirrer,thermometer and dropping funnel was treated in 10 minutes and at −5° C.with a sodium solution bisulfite (41.7 g, 400 mmol) in water (200 mL)and subsequently with n-Bu₄NHSO₄ (678 mg, 2 mmol). The solution wascooled to −5° C. The reaction mixture was stirred at −5 to −0° C. for5-6 hours and subsequently overnight at room temperature. The aqueousphase containing compound V was separated and washed with CH₂Cl₂ (2×20mL).

(2-Cyano-3-(N-Boc)-amino-5-methyl-hexanol (VI)

The above aqueous solution (-250 mL) was added with CH₂Cl₂ (120 mL) andthe reaction mixture was cooled to 0-5° C. on an ice bath. Solid KCN (15g, 230 mmol) was subsequently added to the reaction mixture and thesolution was stirred at room temperature overnight. The organic phasewas separated and the aqueous phase was extracted with CH₂Cl₂. Thecombined organic phases were washed with brine (1×50 mL), dried overMgSO₄ and evaporated to obtain the product as a colourless viscousliquid (43 g). The product had [α]_(D) 51.11 (c=2, MeOH) and was anabout 2:1 mixture of the VI 2(R),3(S) and 2(S),3(S) derivatives. Theyield was 89% compared with the starting L-leucinol.

(2RS,3S)-3-Amino-2-hydroxy-5-methylhexanoic acid (VII)

The mixture of the above crude nitrile VI (43 g) was treated with 150 mlof concentrated HCl (37%) (150 mL) and refluxed overnight to give thecrude acid VII*. The hydrochloric acid excess was removed by rotatoryevaporator and the residue was evaporated with water (100 ML) to removeHCl. The residue was then dissolved in 150 ml of water and added with100 ml of acetone, then treated with 33 ml of a 6.25M NaOH solution toadjust pH to 5. A further amount of acetone (500 mL) was then added tothe solution which was left to stand overnight at 4° C. The precipitatedsolid was subsequently filtered and the solid cake was washed withacetone and dried under vacuum to give crude acid VII (6.5 g) containingan about 3:1 mixture of 2(R),3(S) and 2(S),3(S) derivatives of compoundVI.

The filtrate was evaporated and water was added to adjust the volume ofthe solution to 75 mL.

Acetone (1 L) was then added to the solution which was left to standovernight at 4° C. in refrigerator. The precipitated solid was thenfiltered and the solid cake was washed with acetone and dried undervacuum to give a second amount of product (18 g) containing solid NaClwith an about 1:1 mixture of 2(R),3(S) and 2(S),3(S) derivatives of VII.

The first product VII recovered (22.5 g) was heated in water (120 mL)without obtaining a complete dissolution and then cooled in ice andfiltered to obtain 12.5 g of acid VII still contaminated by about 10 ofundesired 2(R),3(S) derivative of VII. This product was dried and mixedwith the above 1:1 mixture of the second crop crystals (total ˜27 g)

(2RS,3S)-3-(N-Boc)Amino-2-hydroxy-5-methylhexanoic acid (VIII)

(A) The crude acid VI 2(R),3(S), about 90% purity, (2.5 g, 77.6 mmol)was dissolved in a water-THF 1:1 mixture (80 ML), then triethylamine(13.5 mL) and subsequently Boc anhydride (18.5 g, 85 mmol) were added tothe reaction mixture, the whole solution was stirred for 40 hours atroom temperature. The solvent was evaporated by rotatory evaporator, 60ml of water and 60 ml of ethyl acetate were added keeping the wholeunder stirring. The aqueous phase was separated and extracted with ethylacetate (30 mL). The combined organic phases were extracted with 10%aqueous sodium carbonate (30 mL, 20 mL). The basic extract was thencombined with an aqueous phase acidified with 2M hydrochloric acid (˜55mL) to adjust pH of the solution to 2. Acid VIII was then extracted fromthe aqueous phase with ethyl acetate (3×40 mL) and the heteroaceticextracts were washed with water (20 mL), dried (MgSO₄) and evaporated togive the crude VIII Boc derivative as syrup (20 g, 99%).

(B) The crude acid VII 2R,3S, with purity of about 50%, contaminated byNaCl (27 g), was dissolved in a water-dioxane 1:1 mixture (120 mL).Triethylamine (20 mL) was then added to the reaction mixture, then Bocanhydride (26.16 g, 120 mmol). The solution was stirred for 40 hours atroom temperature. The solvent was evaporated by rotatory evaporator andwater (100 mL) and ethyl acetate (100 mL) were added to the residuekeeping stirring for a further few minutes. The organic phase wasseparated and extracted with 10% aqueous sodium carbonate (45 mL, 30mL). The sodium carbonate extracts were then combined with the aqueousphase, acidified with 1M hydrochloric acid (˜165 mL) and extracted withethyl acetate (3×60 mL), afterwards washed with water (30 mL), dried(MgSO₄) and evaporated to give the crude VII Boc as syrup (16 g),consisting of a 1:1 mixture of the 2R,3S and 2S,3S isomers.

(2R,3S)-3-(N-Boc)Amino-2-hydroxy-5-methylhexanoic acid methyl ester (IX)

Diazomethane was prepared from diazald following the process reported inT. H. Black [Aldrichimica Acta, 16, 3 (1983)].

(A) A solution of the crude acid VIII (20 g, 56.6 mmol) in CH₂Cl₂ (75mL) was slowly added to a cold diazomethane ethereal solution (˜77 mmol)and the mixture was left for two hours on ice bath. The colour of thesolution in that step turned white thus indicating that mostdiazomethane had been adsorbed. The solution was then concentrated andthe residue crystallized from a mixture of toluene (20 mL) and hexane(70 mL). After cooling overnight in refrigerator at 4° C., the crystalsof the pure IXA 2R,3S derivative were collected by filtration. The yieldwas 15 g. The mother liquors gave about 5 g of a 1:1 isomeric mixture.

(B) Using the same procedure, a 1:1 mixture of acid VIII (16 g) wastransformed into a 1:1 mixture of IXA and IXB esters. The material frommother liquors (5 g from step A) was added and the material was combinedand separated by column chromatography using hexane-ethyl acetate aseluent (9:1 to 7:3). Ninhydrine was used as developer for the TLCplates. The apolar compound, Rf 0.75 (hexanoethyl acetate: 7:3) wasidentified as the desired ester IXA (2R,3S), which was recrystallizedfrom cyclohexane to give IXA as colorless needles (8 g) m.p. 95-96° C.,[α]_(D) 72.4° (c=1, MeOH).

The polar compound, Rf 0.5 (hexane-ethyl acetate 7:3) was identified asIXB (2S,3S) and was recrystallized from cyclohexane to give 10 g of IXBas colorless needles.

2,4-dimethoxybenzaldehydedimethyl acetal

A mixture of 2,4-dimethoxybenzaldehyde (41.25 g, 0.25 mols), anhydroustrimethyl orthoformate (50 mL) and ammonium nitrate (2 g dissolved in 20ml of methanol) was refluxed for 6 hours (¹HNMR of the reaction mixtureshowed a 65-70% conversion). At first, the hot reaction mixture was aclear solution, but as the reaction progressed the solid precipitated. Asecond portion of anhydrous trimethyl orthoformate (20 mL) was added andpart of methanol was distilled off.

When the temperature of the reaction mixture reached 95-100° C., all thesolid dissolved in the flask. The solution was cooled to roomtemperature and added with anhydrous Na₂CO₃ (5 g), stirring for 30 min.Subsequently the solution was filtered and the residue was distilled byfractional distillation under vacuum at 0.25 mmHg. The first fraction atlow temperature mainly consisted of the trimethyl orthoformate excessand the second fraction, which distilled as colourless oil at 175-180°C., was the desired acetal. Yield: 37 g (70%).

(4S,5R)-N-Boc-2-(2,4-Dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylicacid methyl ester (X)

A solution of (2R, 3S)-3-(N-Boc)amino-2-hydroxy-5-methylhexanoic acidmethyl ester (IXA) (34.375 g, 125 mmol) in anhydrous THF (150 ml) wasadded with distilled 2,4-dimethoxybenzaldehyde dimethyl acetal (30 g,142 mmol) and subsequently pyridinium p-toluenesulfonate (Py.Tos; 400mg).

The solution was heated under mild reflux in a 500 ml three-necked flaskequipped with a Dean-Stark separator. After about 6 hours under reflux,about 60 ml of THF containing methanol generated during the reactionwere removed. A sample was taken for ¹H NMR analysis (in CDCl₃). Thepeak at δ=1.41 ppm disappeared (1) and a novel peak appeared at δ=1.24ppm for the protected methyl ester (2). After 6 hour reflux, theconversion was about 70-75%.

A fresh aliquot of anhydrous THF (50 ml) was added, then an amount of2,4-dimethoxybenzaldehyde acetal (5.0 g; 24 mmol). The reaction mixturewas refluxed for a further 2.5 hours, during which time about 50 ml ofTHF were removed using the Dean-Stark apparatus. The subsequent ¹H NMRanalysis showed the complete transformation of the starting material.

The reaction mixture was added with a NaHCO₃ saturated aqueous solution(15 ml) and the mixture was stirred for 15 minutes to neutralize Py.Tos.t-Butyl methyl ether (85 ml) and water (15 ml) were subsequently addedand the organic phase was separated. The aqueous phase was extractedwith t-butyl methyl ether (20 ml) and the combined organic phases werewashed with water (30 ml) and evaporated to a residue (66 g) of crudeproduct X.

Hydrolysis of Ester X to Give Acid XI

The crude ester X (22 g, 42 mmol) was dissolved in 100 ml of methanoland added with water (50 ml) containing 8.7 g of potassium carbonate.After stirring overnight at room temperature, the reaction wasconsidered completed by TLC monitoring (toluene-ethyl acetate: 4.5:1).TLC analysis was confirmed by ¹H NMR analysis, checking thedisappearance of the methyl ester peak.

Methanol was evaporated at a temperature not above 40° C. under vacuum(about 60 g residue) and water (150 ml) was added to the residue. Theaqueous suspension was extracted with ethyl acetate (5×50 ml) to removethe benzaldehyde and benzaldehyde dimethyl acetal excess. 90 ml ofmethylene chloride were added to the aqueous phase, the mixture wascooled on ice bath and the diphasic system was treated with about 125 mlof 1M NaHSO₄ (pH=3) under strong stirring. The phases were separated andthe aqueous phase was extracted with methylene chloride (75 ml). Thecombined methylene chloride extracts were washed with water (30 ml),brine (30 ml) and dried over MgSO₄. The solution was then kept at −60°C. until next use. The yield in the final product as colourless solidwas of 16 g, about 93% based on the starting product.

EXAMPLE 4 Preparation of 14β-hydroxy-7-Tes baccatine III 1,4 carbonate

A solution of 11.2 g of 10-deacetyl-14-hydroxybaccatine III in 50 ml ofdry tetrahydrofuran was added with 0.72 g of CeCl₃.7H₂O and 7.3 ml ofacetic anhydride. The reaction mixture was stirred at room temperaturefor 5 hours; during this time the mixture became homogeneous. 10 g ofice were added and the whole was stirred for 1 hour. Tetrahydrofuran wasevaporated off under vacuum and the residue was diluted with 200 ml ofH₂O. The precipitate was filtered and dried under vacuum in the presenceof P₂O₅; the product was crystallized from ethyl acetate to obtain 10 gof 14-hydroxybaccatine III having the following characteristics:

Mp: 236-8° C.; IR (KBr): 3474, 1739, 1400, 1240, 1090, 1049 cm⁻¹.

¹H NMR (CDCl₃, 200 MHz); 8.07 (d, J=8 Hz, Bz), 7.55 (d, J=8 Hz, Bz),7.44 (t, J=8 Hz, Bz), 6.31 (s, H-10), 5.80 (d, J=7 Hz, H-2), 4.97 (br d,J=8 Hz, H-5), 4.73 (br, d, J=4 Hz, H-13), 4.41 (m, H-7), 4.24 (d, J=4Hz, H-14), 4.20 (d, J=7 Hz, H-20a), 4.06 (d, J=7 Hz, H-20b), 3.89 (J 0(Hz, H-3), 2.29 (s, OAc), 2.22 (s, OAc), 2.04 (s, H-18), 1.66 (s, H-19),1.25, 1.11 (s, H-16 and H-17).

In a four-necked flask equipped with stirrer, dropping funnel,thermometer and reflux condenser cooled to −12° C., were placed 52.8 mlof a 1.9M solution of phosgene in toluene. This solution was dropwiseadded with 11.6 g of 14-hydroxy baccatine III dissolved in 53 ml ofmethylene chloride and 17.5 ml of pyridine under stirring in 30 minutes.Temperature was kept between −6 and −10° C. After 30 minutes 50 ml ofNaHCO₃ saturated solution were added under stirring keeping a tightcontrol of the temperature. After warming to room temperature, thephases were separated. The aqueous phase was contraextracted withmethylene chloride and the organic phases were washed with 45 ml of 2NHCl adjusting pH to about 1. The organic phase was washed with 0.1N HCland then with NaHCO₃, then dried over Na₂SO₄ and evaporated to drynessto quantitatively obtain 11.5 g of 14-hydroxybaccatine-1,14 carbonate.

11.5 g of 14-hydroxybaccatine-1,14 carbonate were dissolved in 50 ml ofDMF and 1 l equivalents of chlorotriethylsilane and 3 equivalents ofN-methyl-imidazole were added at room temperature. After completion ofthe reaction, the mixture was poured into 500 ml of H₂O and theprecipitate was filtered and washed thoroughly with H₂O, then dried toobtain 12.8 g of 14β-hydroxy-7-Tes-baccatine III-1,14 carbonate with thesame characteristics as those reported in example 1.

EXAMPLE 5 Synthesis of 13-(N-Boc-L-isobutylserinyl)-14β-hydroxybaccatineIII, 1,14 carbonate

Starting from 14β-hydroxy-7-Tes-baccatine III-1,14 carbonate obtained asdescribed in the above example, the procedure was as follows.

In a 1 L round-bottom flask were placed 20 g of14β-hydroxy-7-Tes-1,14-carbonate-baccatine III together with 300 ml ofstrictly anhydrous toluene; 10 g of (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylicacid dissolved in CH₂Cl₂ and 2 g of N,N-dimethylaminopyridine (DMAP)were added and 9.5 g of dicyclohexylcarbodiimide (DCC) were added. Thereaction mixture was refluxed for 3 h, then cooled to precipitate offthe ureic product and mother liquors were washed with a NaHCO₃ saturatedsolution to remove the unreacted acid, then with diluted hydrochloricacid to remove DMAP and finally again with NaHCO₃ to neutrality. Theorganic phase was concentrated to dryness to obtain 41.5 g of productwhich could be directly used in the subsequent step.

40 g of this compound were deprotected in two steps by cleaving firstTes and then 2,4-dimethoxybenzaldehyde. 40 g of the compound weredissolved in 100 ml of an acetonitrile/pyridine mixture (80:100) undernitrogen and the mixture was cooled to 0° C.; 13 ml of pyridiniumfluoride were added and the whole was left under stirring for 24 h. Thesolution was poured into 2 L of water and the product was filtered anddried under vacuum. The residue was dissolved in 60 ml of methylenechloride and this solution was added with 40 ml of Methanol HCl 0.6Nunder strong stirring and at 0° C. The reaction mixture was left for 2 hunder stirring, then diluted with 150 ml of methylene chloride andshaken with a NaHCO₃ solution adjusting pH to 6-7. The organic phase wasconcentrated to dryness and the residue was crystallized from acetonehexane, then dried to obtain 16.5 g of13-(N-Boc-β-isobutylisoserinyl)-14β-hydroxybaccatine III 1,14-carbonate.

1. A compound of Formula I,


2. A process for preparing a compound of Formula I,

comprising reacting13-(N-Boc-β-isobutylisoserinyl)-14β-hydroxy-baccatine III 1,14-carbonatewith diazabicyclo[5,4,0]7-undecene in methanol or THF.
 3. A method oftreating cancer selected from the group consisting of breast, ovarianand colon cancer in a patient in need thereof comprising administeringto said a patient having breast, ovarian, or colon cancer atherapeutically effective amount of a compound of claim
 1. 4. The methodof claim 3, wherein the compound is administered in an amount of from 50to 500 mg/m².
 5. A pharmaceutical composition comprising the compound ofclaim 1 and one or more pharmaceutically acceptable carriers and/orexcipients.
 6. The method of claim 3 wherein the cancer is breastcancer.
 7. The method of claim 3 wherein the cancer is ovarian cancer.8. The method of claim 3 wherein the cancer is colon cancer.
 9. Aprocess for preparing a compound of Formula I,

comprising preparing ( 4S, 5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4-isobutyl- 1 -oxazolidine- 5 -carboxylic acid, comprising the steps of:a. protecting the amino group of a leucinol with Boc to formN-Boc-L-leucinol; b. converting the N-Boc-L-leucinol intoN-Boc-L-leucinal; c. preparing a cyanhydrin nitrile from theN-Boc-L-leucinal; d. transforming the cyanhydrin nitrile into acarboxylic acid; e. forming a methyl ester of the carboxylic acid; f.purifying the methyl ester of the carboxylic acid; g. condensing theproduct of step (f) with 2,4 -dimethoxybenzaldehyde dimethyl acetal toform ( 4S, 5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1-oxazolidine- 5 -carboxylic acid methyl ester; h. transforming the ( 4S,5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5-carboxylic acid methyl ester into the ( 4S, 5R)-N-Boc- 2 -( 2,4-dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5 -carboxylic acid; andi. using the ( 4S, 5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1-oxazolidine- 5 -carboxylic acid to prepare the compound of Formula I.10. The process of claim 2, wherein the 13-(N-Boc-β-isobutylisoserinyl)-14 β-hydroxy-baccatine III 1,14 -carbonate is prepared by a processcomprising the steps of: a. reacting 14 β-hydroxy- 10 -deacetylbaccatineIII with a silylating agent to provide a 7 -triethylsilyl 14 β-hydroxy-10 -deacetylbaccatine III; b. reacting the 7 -triethylsilyl 14β-hydroxy- 10 -deacetylbaccatine III with phosgene to provide a 1,14carbonate 7 -triethylsilyl 14 β-hydroxy- 10 -deacetylbaccatine III; c.reacting the 1,14 carbonate 7 -triethylsilyl 14 β-hydroxy- 10-deacetylbaccatine III with a LiHMDS to provide a lithium salt of the 10-hydroxyl group of the 1,14 carbonate 7 -triethylsilyl 14 β-hydroxy- 10-deacetylbaccatine III; d. reacting the lithium salt of the 10 -hydroxylgroup of the 1,14 carbonate 7 -triethylsilyl 14 β-hydroxy- 10-deacetylbaccatine III with an acetylating agent to acetylate the 10-hydroxyl group to provide a 1,14 carbonate 7 -triethylsilyl 14β-hydroxy- 10 -acetylbaccatine III; e. reacting the 1,14 carbonate 7-triethylsilyl 14 β-hydroxy- 10 -acetylbaccatine III with ( 4S,5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5-carboxylic acid to form a C- 13 esterified 1,14 carbonate 7-triethylsilyl 14 β-hydroxy- 10 -acetylbaccatine III; and f. removingthe 7 -triethylsilyl group from the C- 13 esterified 1,14 carbonate 7-triethylsilyl 14 β-hydroxy- 10 -acetylbaccatine III to provide a C- 13esterified 1,14 carbonate 7 -hydroxy 14 β-hydroxy- 10 -acetylbaccatineIII; and g. removing a dimethoxybenzylidene group from the C- 13esterified 1,14 carbonate 7 -hydroxy 14 β-hydroxy- 10 -acetylbaccatineIII to provide 13 -(N-Boc-β-isobutylisoserinyl)- 14 β-hydroxy-baccatineIII 1,14 -carbonate.
 11. The process of claim 10, wherein the silylatingagent is triethyl chlorosilane.
 12. The process of claim 10, wherein the7-triethylsilyl 14 β-hydroxy- 10 -deacetylbaccatine III is reacted withphosgene by dissolving the 7 -triethylsilyl 14 β-hydroxy- 10-deacetylbaccatine III in a methylene chloride/pyridine mixture in a 3:1ratio and then adding a toluene solution containing phosgene to themethylene chloride/pyridine mixture under a nitrogen atmosphere.
 13. Theprocess of claim 10, wherein the 1,14 carbonate 7-triethylsilyl 14β-hydroxy- 10 -deacetylbaccatine III is reacted with LiHMDS in anhydrousTHF.
 14. The process of claim 10, wherein the lithium salt of the10-hydroxyl group of the 1,14 carbonate 7 -triethylsilyl 14 β-hydroxy-10 -deacetylbaccatine III is acetylated with acetyl chloride.
 15. Theprocess of claim 10, wherein the 1,14 carbonate 7-triethylsilyl 14β-hydroxy- 10 -acetylbaccatine III is reacted with the ( 4S, 5R)-N-Boc-2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5 -carboxylicacid in an anhydrous apolar organic solvent in the presence of a baseand of a condensing agent.
 16. The process of claim 15, wherein thecondensing agent is dicyclohexylcarbodiimide.
 17. The process of claim10, wherein the 7-triethylsilyl group is removed from the C- 13esterified 1,14 carbonate 7 -triethylsilyl 14 β-hydroxy- 10-acetylbaccatine III with pyridinium fluoride in anacetonitrile/pyridine solution under nitrogen, and thedimethoxybenzylidene group is removed from the C- 13 esterified 1,14carbonate 7 -hydroxy 14 β-hydroxy- 10 -acetylbaccatine III in amethylene chloride solvent by addition of methanolic HCl followed byaddition of NaHCO ₃.
 18. The process of claim 10, wherein the ( 4S,5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5-carboxylic acid is prepared by the process comprising the steps of: a.protecting the amino group of a leucinol with Boc to formN-Boc-L-leucinol; b. converting the N-Boc-L-leucinol intoN-Boc-L-leucinal; c. preparing a cyanhydrin nitrile from theN-Boc-L-leucinal; d. transforming the cyanhydrin nitrile into acarboxylic acid; e. forming a methyl ester of the carboxylic acid; f.purifying the methyl ester of the carboxylic acid; g. condensing theproduct of step (f) with 2,4 -dimethoxybenzaldehyde dimethyl acetal toform ( 4S, 5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl) 4 -isobutyl- 1-oxazolidine- 5 -carboxylic acid methyl ester; and h. transforming the (4S, 5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine-5 -carboxylic acid methyl ester into the ( 4S, 5R)-N-Boc- 2 -( 2,4-dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5 -carboxylic acid. 19.The process of claim 2, wherein the 13-(N-Boc-β-isobutylisoserinyl)- 14β-hydroxy-baccatine III 1,14 -carbonate is prepared by a processcomprising the steps of: a. acetylating the C- 10 hydroxyl of 14β-hydroxy- 10 -deacetylbaccatine III to provide 14 β-hydroxy- 10-acetylbaccatine III: b. reacting 14 β-hydroxy- 10 -acetylbaccatine IIIwith phosgene to provide a 1,14 carbonate derivative of 14 β-hydroxy- 10-acetylbaccatine III; c. silylating the C- 7 hydroxyl of the 1,14carbonate derivative of 14 β-hydroxy- 10 -acetylbaccatine III to providea 7 -silyl 1,14 carbonate derivative of 14 β-hydroxy- 10-acetylbaccatine III; d. reacting the 7 -silyl 1,14 carbonate derivativeof 14 β-hydroxy- 10 -acetylbaccatine III with ( 4S,5R)-N-Boc- 2 -( 2,4-dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5 -carboxylic acid toprovide a C- 13 esterified 7 -silyl 1,14 carbonate derivative of 14β-hydroxy- 10 -acetylbaccatine III; e. removing the 7 -silyl group fromthe C- 13 esterified 7 -silyl 1,14 carbonate derivative of 14 β-hydroxy-10 -acetylbaccatine III to provide a C- 13 esterified 7 -hydroxy 1,14carbonate derivative of 14 β-hydroxy- 10 -acetylbaccatine III; and f.removing a dimethoxybenzylidene group from the C- 13 esterified 7-hydroxy 1,14 carbonate derivative of 14 β-hydroxy- 10 -acetylbaccatineIII to provide 13 -(N-Boc-β-isobutylisoserinyl)- 14 β-hydroxy-baccatineIII 1,14 -carbonate.
 20. The process of claim 19, wherein the C- 10hydroxyl of 14 β-hydroxy- 10 -deactylbaccatine III is acetylated withacetic anhydride in the presence of a cerium, scandium, or ytterbiumsalt.
 21. The process of claim 20, wherein the salt is CeCl₃.H₂O. 22.The process of claim 19, wherein 14β-hydroxy- 10 -acetylbaccatine III isreacted with phosgene by dissolving the 14 β-hydroxy- 10-acetylbaccatine III in a methylene chloride/pyridine mixture in a 3:1ratio and then adding a toluene solution containing phosgene to themethylene chloride/pyridine mixture under a nitrogen atmosphere.
 23. Theprocess of claim 19, wherein the C- 10 hydroxyl of 14 β-hydroxy- 10-deacetylbaccatine III is acetylated with acetyl chloride.
 24. Theprocess of claim 19, wherein the 7-silyl 1,14 carbonate derivative of 14β-hydroxy- 10 -acetylbaccatine III is reacted with ( 4S, 5R)-N-Boc- 2 -(2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5 -carboxylic acidin an anhydrous apolar organic solvent in the presence of a base and acondensing agent.
 25. The process of claim 24, wherein the condensingagent is dicyclohexylcarbodiimide.
 26. The process of claim 19, whereinthe silyl protective group is removed from the C- 13 esterified 7 -silyl1,14 carbonate derivative of 14 β-hydroxy- 10 -acetylbaccatine III withpyridinium fluoride in a acetonitrile/pyridine solution under nitrogen,and the dimethoxybenzylidene group is removed from the C- 13 esterified7 -hydroxy 1,14 carbonate derivative of 14 β-hydroxy- 10-acetylbaccatine III in a methylene chloride solvent by addition ofmethanolic HCl followed by addition of NaHCO ₃.
 27. The process of claim19, wherein the ( 4S,5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl-1 -oxazolidine- 5 -carboxylic acid is prepared by the process comprisingthe steps of: a. protecting the amino group of a leucinol with Boc toform N-Boc-L-leucinol; b. converting the N-Boc-L-leucinol intoN-Boc-L-leucinal; c. preparing a cyanhydrin nitrile from theN-Boc-L-leucinal; d. transforming the cyanhydrin nitrile into acarboxylic acid; e. forming a methyl ester of the carboxylic acid; f.purifying the methyl ester of the carboxylic acid; g. condensing theproduct of step (f) with 2,4 -dimethoxybenzaldehyde dimethyl acetal toform ( 4S, 5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl) 4 -isobutyl- 1-oxazolidine- 5 -carboxylic acid methyl ester; and h. transforming the (4S, 5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine-5 -carboxylic acid methyl ester into the ( 4S, 5R)-N-Boc- 2 -( 2,4-dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5 -carboxylic acid. 28.The process of claim 2, wherein the 13-(N-Boc-β-isobutylisoserinyl)- 14β-hydroxy-baccatine III 1,14 -carbonate is prepared by a processcomprising the steps of: a. transforming 14 β-hydroxy- 10-deacetylbaccatine III into a triethylsilylated derivative at the 7-position; b. preparing a 1,14 carbonate derivative from the product ofstep (a); c. selectively acetylating the 10 -hydroxyl; d. reacting theproduct of step (c) with ( 4S, 5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4-isobutyl- 1 -oxazolidine- 5 -carboxylic acid; e. cleaving thetriethylsilyl and dimethoxybenzylidene protective groups from theproduct of step (d).
 29. The process of claim 28, wherein the silylatingagent of step (a) is triethyl chlorosilane; the 1,14 carbonatederivative in step (b) is prepared using phosgene in toluene in a 3:1methylene chloride/pyridine solution under nitrogen atmosphere; step (c)is carried out with LiHMDS in anhydrous THF, and the resulting 10-hydroxy derivative is subsequently acetylated with acetyle chloride;step (d) is carried out in anhydrous apolar organic solvent, in thepresence of a base and the condensing agent dicyclohexylcarbodiimide(DCC); the triethylsilyl protective group in step (e) is removed withpyridinium fluoride in acetonitrile/pyridine solution under nitrogen,and the dimethoxybenzylidene protective group is removed in methylenechloride solvent by addition of HCl in methanol and subsequentlyaddition of NaHCO ₃.
 30. The process of claim 28, wherein the (4S,5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5-carboxylic acid is prepared by the process comprising the steps of: a.protecting the amino group of a leucinol with Boc to formN-Boc-L-leucinol; b. converting the N-Boc-L-leucinol intoN-Boc-L-leucinal; c. preparing a cyanhydrin nitrile from theN-Boc-L-leucinal; d. transforming the cyanhydrin nitrile into acarboxylic acid; e. forming a methyl ester of the carboxylic acid; f.purifying the methyl ester of the carboxylic acid; g. condensing theproduct of step (f) with 2,4 -dimethoxybenzaldehyde dimethyl acetal toform ( 4S, 5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl) 4 -isobutyl- 1-oxazolidine- 5 -carboxylic acid methyl ester; and h. transforming the (4S, 5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine-5 -carboxylic acid methyl ester into the ( 4S, 5R)-N-Boc- 2 -( 2,4-dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5 -carboxylic acid. 31.The process of claim 2, wherein the 13-(N-Boc-β-isobutylisoserinyl)- 14β-hydroxy-baccatine III 1,14 -carbonate is prepared by a processcomprising the steps of: a. selectively acetylating the hydroxyl at theC- 10 of 14 β-hydroxy- 10 -deacetylbaccatine III; b. preparing a 1,14carbonate derivative from the product of step (a); c. silylating thehydroxyl at C- 7; d. reacting the product of step (c) with ( 4S,5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5-carboxylic acid; e. cleaving the triethylsilyl and dimethoxybenzylideneprotective groups from the product of step (d).
 32. The process of claim31, wherein step (a) is carried out with acetic anhydride in thepresence of a cerium, scandium or ytterbium salt, the 1,14 carbonatederivative in step (b) is prepared using phosgene in toluene in a 3:1methylene chloride/pyridine solution under nitrogen atmosphere; step (c)is carried out with LiHMDS in anhydrous THF, and the resulting 10-hydroxy derivative is subsequently acetylated with acetyle chloride;step (d) is carried out in anhydrous apolar organic solvent, in thepresence of a base and the condensing agent dicyclohexylcarbodiimide(DCC); the triethylsilyl protective group in step (e) is removed withpyridinium fluoride in acetonitrile/pyridine solution under nitrogen,and the dimethoxybenzylidene protective group is removed in methylenechloride solvent by addition of HCl in methanol and subsequentlyaddition of NaHCO ₃.
 33. The process of claim 32, wherein the ceriumsalt comprises CeCl₃ 7H ₂ O.
 34. The process of claim 31, wherein the (4S,5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5-carboxylic acid is prepared by the process comprising the steps of: a.protecting the amino group of a leucinol with Boc to formN-Boc-L-leucinol; b. converting the N-Boc-L-leucinol intoN-Boc-L-leucinal; c. preparing a cyanhydrin nitrile from theN-Boc-L-leucinal; d. transforming the cyanhydrin nitrile into acarboxylic acid; e. forming a methyl ester of the carboxylic acid; f.purifying the methyl ester of the carboxylic acid; g. condensing theproduct of step (f) with 2,4 -dimethoxybenzaldehyde dimethyl acetal toform ( 4S, 5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl) 4 -isobutyl- 1-oxazolidine- 5 -carboxylic acid methyl ester; and h. transforming the (4S,5R)-N-Boc- 2 -( 2,4 -dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5-carboxylic acid methyl ester into the ( 4S, 5R)-N-Boc- 2 -( 2,4-dimethoxyphenyl)- 4 -isobutyl- 1 -oxazolidine- 5 -carboxylic acid.